Inflammation in Treatment-Resistant Depression: From Mechanisms to Therapeutics

Depression is a prevalent and debilitating mental disorder, imposing a leading global public health burden. First-line monoamine-based antidepressants are ineffective in a substantial proportion of patients, many of whom develop treatment-resistant depression (TRD). Emerging evidence strongly implicates inflammation in the pathophysiology of TRD, with a heightened inflammatory profile observed in patients who respond poorly to conventional therapies. Consequently, targeting inflammatory pathways represents a promising novel therapeutic strategy for TRD. This review examines the interplay between inflammation and TRD, elucidates the mechanisms by which inflammation contributes to depression, and evaluates current anti-inflammatory interventions and their regulatory mechanisms. A particular focus is placed on the pivotal role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of TRD and the potential of anti-TNF-α monoclonal antibodies as a targeted treatment. We propose that TNF-α serves not only as a promising therapeutic target but also as a valuable biomarker for TRD treatment. These perspectives may pave the way for precision medicine in TRD and inspire novel therapeutic approaches for depression. • A central role for inflammation in the pathophysiology of treatment-resistant depression (TRD) was established. • How chronic inflammation disrupts neurotransmission, neuroplasticity, HPA axis function, and glial homeostasis to drive depressive symptoms and treatment resistance were delineated. • A key focus is placed on the role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of TRD. • The therapeutic potential and mechanistic basis of anti-inflammatory strategies, particularly anti-TNF-α monoclonal antibodies, for TRD are evaluated. • Current challenges and future directions for biomarker-driven, precision medicine approaches in inflammation-targeted TRD therapy were identified.